Tricyclic-cyclic amines as novel cholinesterase inhibitors

Abstract

Compounds of the formula ##STR1## wherein ring A, ring B, ring D, R 2 , R 3 , R 4 , R 5 , R 6 ,R 11 , R 12 , R 13 , E, G, X and P are as defined below. The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease.

I claim: 
     
       1. A compound of the formula ##STR29## wherein P is ##STR30## ring A is benzo, thieno, pyrido, or pyrrolo; R 2  is hydrogen or (C 1  -C 4 ) alkyl; R 3 , R 4 , R 5  and R 6  are each independently selected from hydrogen, (C 1  -C 6 ) alkoxy, benzyloxy, hydroxy, halo, (C 1  -C 6 )alkyl and SO 2  CH 2  -phenyl;   G is carbon or nitrogen;   E is carbon, nitrogen, oxygen, or sulfur;   the curved dashed line in ring B represents one double bond, so that ring B contains two double bonds;   each of the straight dashed lines connecting, respectively, the carbon to which P is attached and X to ring D represents an optional double bond;   the carbon at any of positions 1-3 at ring D may optionally be replaced by nitrogen when such carbon is adjacent to a carbonyl group, the carbon atom of which is at position 1, 2, or 3 of ring D, so that ring D is a lactam ring;   X is O, S, NOR 1  hydrogen or (C 1  -C 6 ) alkyl with the proviso that X is double bonded to ring D only when the member of ring D to which it is bonded is carbon and X is 0, S or NOR 1  ;   R 1  is hydrogen or (C 1  -C 6 ) alkyl;   q is an integer from 1 to 2;   n is an integer from 1 to 3 when ring D is a lactam ring, and n is an integer from 0 to 3 when ring D is not a lactam ring;   M is carbon or nitrogen;   L is phenyl-(C 1  -C 6 )alkyl;   R 11  is hydrogen, halo, hydroxy, (C 1  -C 4 ) alkyl, (C 1  -C 4 ) alkoxy or oxygen;   R 12  and R 13  are each independently selected from hydrogen, fluoro, hydroxy, acetoxy, O-mesylate, O-tosylate, (C 1  -C 4 )alkyl, and (C 1  -C 4 )alkoxy; or R 12  and R 13  may, together with the atoms to which they are attached, when both of R 12  and R 13  are attached to carbon atoms, form a three, four or five membered ring wherein each atom of said ring is carbon or oxygen;   R 7  and R 8  are each hydrogen;   or R 8  and R 12 , together with the atoms to which they are attached, form a saturated carbocyclic ring containing 4 to 7 carbons wherein one of said carbon atoms may optionally be replaced with oxygen, nitrogen or sulfur;    with the proviso that (a) when E is carbon, nitrogen, oxygen, or sulfur, then G is carbon; (b) when G is nitrogen, then E is carbon or nitrogen; (c) when either E and G are both nitrogen, or G is carbon and E is oxygen or sulfur, then is absent; (d) each of the atoms at positions 1, 2 and 3 of ring D may be bonded by no more than one double bond; and (e) X is attached to the position on ring D that is adjacent to the position to which the hydrocarbon substituent containing P is attached;   and the pharmaceutically acceptable salts thereof.     
     
     
       2. A compound according to claim 1, selected from the group consisting of: 2,3-dihydro-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-6,7-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   
     
     
       2. 3-dihydro-7-fluoro-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one; 2,3-dihydro-7-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-6-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-8-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-di hydro-6-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one; 2,3-di hydro-7-benzyloxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-7-ethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-8-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-7-p-tosyloxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-7-fluoro-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-6,7-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-9-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-7-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-6-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-8-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-6-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   
     
     
       2. 3-dihydro-6-benzyloxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one; 2,3-dihydro-7-ethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-8-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-7-tosyloxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-7-hydroxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-2-methyl-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-7-acetoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one;   2,3-dihydro-1-oxo-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indole-7-ol, methyl carbamate ester;   2,3-dihydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-thione;   2,3-dihydro-7-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-thione;   2,3-dihydro-7-hydroxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-thione;   1,2,3,4-tetrahydro-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-1-one;   1,2,3,4-tetrahydro-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-cyclopent[b]indol-3-one; 1,2,3,4-tetrahydro-4-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-5-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-6-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl methylene]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-8-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl methylene]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl methylene]-cyclopent[b]indol-3-one;   
     
     
       1. 2,3,4-tetrahydro-4-benzoyl-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-cyclopent[b]indol-3-one; 1,2,3,4-tetrahydro-6,7-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-6,7-dimethyl-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-4-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-5-methoxy-2-[[1-(phenylmethyl)-4 piperidinyl]methyl]-cyclopent [b]indol-3-one;   1,2,3,4 -tetrahydro - 6 -methoxy- 2 -[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent [b]indo 1-3-one;   1,2,3,4-tetrahydro-8-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-4-benzyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-7-methoxy-2-[[1-(phenylmethyl)-4 -piperidinyl]methyl]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-4-benzoyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3 -one;   1,2,3,4-tetrahydro-4-tosyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3 -one;   1,2,3,4-tetrahydro-6,7-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3 -one;   1,2,3,4-tetrahydro-6-hydroxy-2-[[1-(phenylmethyl)-4 piperidinyl]methyl]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-7-hydroxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-6,7-dimethyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-one;   1,2,3,4-tetrahydro-4-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-thione;   1,2,3,4-tetrahydro-5-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-thione;   
     
     
       1. 2,3,4-tetrahydro-6-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-thione; 1,2,3,4-tetrahydro-8-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-thione;   1,2,3,4-tetrahydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3 -thione;   1,2,3,4-tetrahydro-6,7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3 -thione;   1,2,3,4-tetrahydro-6-hydroxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3 -thione;   1,2,3,4-tetrahydro-7-hydroxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3 -thione;   1,2,3,4-tetrahydro-6,7-dimethyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-cyclopent[b]indol-3-thione;   2,3-dihydro-6-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-cyclopent[b](benzo [b]furan)-1-one;   2,3-dihydro-6-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-cyclopent[b](benzo [b]furan)-1-one;   2,3-dihydro-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]benzimidazol-1-one;   2,3-dihydro-6-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]]methylene]-1H-cyclopent[b](benzo [b]thieno)-1one;   6,7-dihydro-6-[[1-(phenylmethyl)-4-piperidinyl]methyl]-5H-thieno [3,2-b]-pyrrolizine-5-one;   2,3-dihydro-2 -[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a](thieno[2,3-b]pyrrol)-1-one;   2,3-dihydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a](6-azaindol )-1-one;   2,3-dihydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a](6-azaindol )-1-one;   1,2,3,4-tetrahydro-6-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]ethyl]-pyrrolo[3,4-b]indol-3-one;   1,2,3,4-tetrahydro-6-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]ethyl]-pyrrolo[3,4-b]indol-3-one;   1,2,3,4-tetrahydro-7-methyl-2-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-pyrrolo[3,4-b]indol-3-one;   
     
     
       2. 3-dihydro-1-hydroxy-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indole; 2,3-dihydro-1-hydroxy-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indole;   2,3-dihydro-1-acetoxy-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indole;   
     
     
       2. 3-dihydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-oxime; 1,4-dihydro-7-chloro-2-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]pyrrolo[3,4-b]indol-3(2H)-one;   1,2-dihydro-7-methyl-2-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]pyrrolo[3,4-(benzo[b]thieno)-1H-3-one;   1,2-dihydro-6-methyl-2-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]pyrrolo[3,4-b](benzo[b]thieno) 1H-3-one;   1,2-dihydro-7-chloro-2-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]pyrrolo[3,4-b](benzo[b]thieno)1H-3-one;   2,3-dihydro-5-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-cyclopent[b](benzo[b]thieno)-1-one;   2,3-dihydro-5-methyl-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-cyclopent[b](benzo[b]thieno)-1-one.   
     
     
       3. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
       4. A method of inhibiting cholinesterase in a mammal, comprising administering to a mammal a cholinesterase inhibiting amount of a compound according to claim 1, or a pharmaceutically salt therof. 
     
     
       5. A method of enhancing memory comprising administering to a patient a memory enhancing effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.